US5670653A - Process for the manufacture of (4,5)-trans-oxazolidines - Google Patents

Process for the manufacture of (4,5)-trans-oxazolidines Download PDF

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US5670653A
US5670653A US08/739,565 US73956596A US5670653A US 5670653 A US5670653 A US 5670653A US 73956596 A US73956596 A US 73956596A US 5670653 A US5670653 A US 5670653A
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oxazolidine
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Hans Hilpert
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FHOFFMANN-LA ROCHE AG A SWISS Co
Hoffmann La Roche Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel process for the manufacture of (4,5)-trans-oxazolidines from the corresponding cis compounds.
  • any compound containing a (4,5)-cis-2-oxo-oxazolidine ring is isomerized to the corresponding (4,5)-trans-2-oxo-oxazolidine-containing compound by a process comprising treating the (4,5)-cis compound with a strong base to give the (4,5)-trans compound.
  • the process of the present invention yields the trans-configurated 2-oxo-oxazolidines with high stereoselectivity.
  • the process in accordance with the invention comprises converting a (4,5)-cis-2-oxo-oxazolidinone into the corresponding (4,5)-trans-2-oxo-oxazolidinone by means of a strong base.
  • R 2 is any acid protecting group, preferably alkyl
  • R 3 is any amino protecting group, preferably an amine, amide or urethane protecting group; or hydrogen,
  • any compound which contains a (4,5)-cis-2-oxo-oxazolidine moiety can be isomerized to provide the corresponding (4,5)-trans bond.
  • This process is an important new method for producing a (4,5)-trans-2-oxo-oxazolidine moiety.
  • These compounds are important in the field since they can be intermediates for anticancer, antiviral and antimicrobial agents.
  • compounds of formula II can be converted to compounds of formula I, which are known intermediates for producing pharmaceutically active agents as disclosed in Magnus and Pye (J. Chem. Soc., Chem. Commun., (1995) 1933-1934); U.S. Pat. No. 5,495,025 and Herranz et al. (J.
  • cis-2-oxo-oxazolidines can be prepared, for example, by reacting an ⁇ -hydroxy- ⁇ -aminoacid ester with a corresponding carbonylating agent.
  • carbonylating agents include esters of haloformic acids (phenylchloroformate), carbonyldiimidazole, phosgene, and triphosgene.
  • Cis-2-oxo-oxazolidines are used, for example, in the synthesis of HIV protease inhibitors.
  • Preferred processes are those in which (4,5)-cis-2-oxo-oxazolidines of formula (II) above in which R 2 is lower-alkyl and R 3 is hydrogen or a benzyl, benzoyl, acetyl or allyl group are isomerized.
  • Especially preferred processes are those in which (4,5)-cis-2-oxo-oxazolidines of formula (II) above in which R 2 is lower-alkyl and R 3 is hydrogen are isomerized.
  • reaction isomerization is conveniently carried out at a preferred temperature between -20° C. and +80° C., most preferably between +20° C. and +45° C.
  • any conventional strong base can be utilized.
  • the preferred strong bases are alkali metal or alkaline earth metal alcoholates, i.e. alcoholates in which the hydrocarbon chain comprises alkyl groups as set forth for R 2 , lithium, sodium or potassium amide, alkyllithium compounds or alkylmagnesium halides. Sodium methylate or potassium tert.butylate is preferred.
  • Numerous bases as well as their relative strengths are available in standard treatises and handbooks. Accordingly, other bases suitable for isomerizing cis-2-oxo-oxazolidines to the trans configuration are readily recognized or determined by those of skill in the art.
  • inert solvent refers to a solvent which is inert under the described reaction conditions.
  • solvents such as toluene, tetrahydrofuran (THF) or alcohols corresponding to the groups R 2 , etc. can be used.
  • R 2 can be any conventional organic acid protecting group.
  • These conventional acid protecting groups can be removed at a later stage in the synthesis of pharmaceutically active compounds by methods well known in the art, including acid hydrolysis and catalytic hydrogenation.
  • the preferred organic acid protecting groups are the esters. Any conventional ester that can be hydrolyzed to yield the acid can be utilized as the protecting group.
  • Exemplary esters useful for this purpose are the lower alkyl esters, particularly methyl and ethyl ester, the aryl esters, particularly phenyl ester and the aryl lower alkyl esters, particularly benzyl ester.
  • alkyl alone or in combination relates to a cyclic, branched or straight-chain monovalent hydrocarbon group containing one to twenty four, preferably one to twelve, carbon atoms.
  • lower-alkyl is concerned with straight-chain or branched saturated alkyl groups with 1 to 8, preferably 1-4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, pentyl, hexyl, heptyl, octyl and the like.
  • Alkyl and lower-alkyl groups can optionally carry one or more substituents selected from alkyl, alkoxy, lower-alkyl, halogen, hydroxy, amino, nitro, thio and the like.
  • halogen stands for fluorine, chlorine, bromine or iodine.
  • any conventional amino protecting group can be utilized.
  • These conventional amino protecting groups can be removed by methods well known in the art, including acid hydrolysis and catalytic hydrogenation.
  • These conventional amino protecting groups include lower alkyl carbonyl, aryloxycarbonyl, halo substituted lower alkoxy carbonyl and arylloweralkoxycarbonyl, for example benzyloxycarbonyl, t-butoxycarbonyl, etc.
  • Amine, amide or urethane protecting groups embrace groups such as, for example, benzyl, benzoyl, allyl, acetyl or tert.butoxycarbonyl.
  • isolation and purification of the compounds obtained according to the process in accordance with the invention can be carried out using any suitable separation or purification method, for example by filtration, extraction, crystallization, column chromatography, preparative HPLC, thin-layer chromatography or combinations of these or other procedures which are known from the state of the art.
  • methyl (4S,5S)-4-cyclohexylmethyl-2-oxo-oxazolidine-5-carboxylate obtainable by hydrogenating methyl (4S,5R)-4-benzyl-2-oxo-oxazolidine-5-carboxylate, is reacted under the conditions given in Example 1.
  • Methyl (4S,5R)-4-cyclohexylmethyl-2-oxo-oxazolidine-5-carboxylate is obtained in a yield of about 95%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Compounds containing a (4,5)-cis-2-oxo-oxazolidine ring are isomerized to the corresponding (4,5)-trans-2-oxo-oxazolidine by treating the cis compound with a strong base.

Description

FIELD OF THE INVENTION
The present invention relates to a novel process for the manufacture of (4,5)-trans-oxazolidines from the corresponding cis compounds.
BACKGROUND OF THE INVENTION
These compounds are important intermediates for the manufacture of β-aminocarboxylic acid derivatives which are building bricks for pharmacologically active substances, especially those which are suitable for the treatment of viral infections, for lowering blood pressure and for the control of tumors. Some uses for (4,5)-trans-oxazolidines are summarized for example in Melon et al. (1992), Bull. Soc. Chim. Fr., 129, 585-593. The compounds of the present invention are useful for the synthesis of renin inhibitors, bestatin, amastatin and HIV-1 protease inhibitors.
Herranz et al. (J. Org. Chem. (1990) 55, 2232-2234) describe a synthesis of (2S,3R)-3-amino-2-hydroxy-phenylbutyric acid esters using a trimethylsilyl-protected cyanohydrin for the production of bestatin and amastatin.
Patel et al. (J. Med. Chem. (1993) 36, 2431-2447) describe the preparation of renin inhibitors based on activated ketones. In the synthesis of the 2-oxo-oxazolidine intermediates an expensive working-up of the corresponding precursors by chromatography and crystallization is required.
Further synthetic routes for the preparation of (4,5)-trans-2-oxo-oxazolidines are described, for example, by Melon et el. (Bull. Soc. Chim. Fr. (1992) 129, 585-593).
SUMMARY OF THE INVENTION
In accordance with this invention, any compound containing a (4,5)-cis-2-oxo-oxazolidine ring is isomerized to the corresponding (4,5)-trans-2-oxo-oxazolidine-containing compound by a process comprising treating the (4,5)-cis compound with a strong base to give the (4,5)-trans compound.
It has now surprisingly been found that the process of the present invention yields the trans-configurated 2-oxo-oxazolidines with high stereoselectivity. The process in accordance with the invention comprises converting a (4,5)-cis-2-oxo-oxazolidinone into the corresponding (4,5)-trans-2-oxo-oxazolidinone by means of a strong base.
Specific embodiments of this invention involve the isomerization of (4,5)-cis-2-oxo-oxazolidines of formula (II) ##STR1## wherein R1 is isobutyl or benzyl;
R2 is any acid protecting group, preferably alkyl; and
R3 is any amino protecting group, preferably an amine, amide or urethane protecting group; or hydrogen,
comprising treating compounds of formula (II) with a strong base to give compounds of formula (I) ##STR2## in which R1, R2 and R3 in formula (I) are as defined above.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with this invention, any compound which contains a (4,5)-cis-2-oxo-oxazolidine moiety can be isomerized to provide the corresponding (4,5)-trans bond. This process is an important new method for producing a (4,5)-trans-2-oxo-oxazolidine moiety. These compounds are important in the field since they can be intermediates for anticancer, antiviral and antimicrobial agents. For instance, compounds of formula II can be converted to compounds of formula I, which are known intermediates for producing pharmaceutically active agents as disclosed in Magnus and Pye (J. Chem. Soc., Chem. Commun., (1995) 1933-1934); U.S. Pat. No. 5,495,025 and Herranz et al. (J. Org. Chem. (1990) 55, 2232-2234). Magnus and Pye (J. Chem. Soc.) describe a reaction sequence for the manufacture of taxol derivatives. Here, the taxol side-chain on ring system A can be introduced by simple esterification with the compounds in accordance with the invention, with the correct stereochemistry being obtained in one reaction step. U.S. Pat. No. 5,495,025 describes the synthesis of 2- 3(S)-amino-2(R)-hydroxy-4-phenylbutyl!-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, which is useful as an intermediate in the chemical synthesis of certain anti-retroviral compounds. Herranz et al. (J. Org. Chem. (1990) 55, 2232-2234 describe the synthesis of (2S,3R)-3-amino-2-hydroxy acids, which are intermediates for the aminopeptidase inhibitors Bestatin and Amastatin, which possess antitumor and antimicrobial activities.
Please note U.S. Pat. No. 5,495,025, European Patent Publication No. EP 0635493, and Herranz, et al. (J. Org. Chem. (1990) 55, 2232-2234. Thus, cis-2-oxo-oxazolidines can be prepared, for example, by reacting an α-hydroxy-β-aminoacid ester with a corresponding carbonylating agent. Examples of carbonylating agents include esters of haloformic acids (phenylchloroformate), carbonyldiimidazole, phosgene, and triphosgene. Cis-2-oxo-oxazolidines are used, for example, in the synthesis of HIV protease inhibitors.
Preferred processes are those in which (4,5)-cis-2-oxo-oxazolidines of formula (II) above in which R2 is lower-alkyl and R3 is hydrogen or a benzyl, benzoyl, acetyl or allyl group are isomerized. Especially preferred processes are those in which (4,5)-cis-2-oxo-oxazolidines of formula (II) above in which R2 is lower-alkyl and R3 is hydrogen are isomerized.
In carrying out the issomerization process of this invention, temperature is not critical. The reaction isomerization is conveniently carried out at a preferred temperature between -20° C. and +80° C., most preferably between +20° C. and +45° C.
In carrying out the isomerization process of this invention, any conventional strong base can be utilized. Among the preferred strong bases are alkali metal or alkaline earth metal alcoholates, i.e. alcoholates in which the hydrocarbon chain comprises alkyl groups as set forth for R2, lithium, sodium or potassium amide, alkyllithium compounds or alkylmagnesium halides. Sodium methylate or potassium tert.butylate is preferred. Numerous bases as well as their relative strengths are available in standard treatises and handbooks. Accordingly, other bases suitable for isomerizing cis-2-oxo-oxazolidines to the trans configuration are readily recognized or determined by those of skill in the art.
The process is carried out in any conventional inert solvent, which will be familiar to any person skilled in the art. The term "inert solvent" refers to a solvent which is inert under the described reaction conditions. For example, solvents such as toluene, tetrahydrofuran (THF) or alcohols corresponding to the groups R2, etc. can be used.
In the specific oxazolidine of formula II, R2 can be any conventional organic acid protecting group. These conventional acid protecting groups can be removed at a later stage in the synthesis of pharmaceutically active compounds by methods well known in the art, including acid hydrolysis and catalytic hydrogenation. The preferred organic acid protecting groups are the esters. Any conventional ester that can be hydrolyzed to yield the acid can be utilized as the protecting group. Exemplary esters useful for this purpose are the lower alkyl esters, particularly methyl and ethyl ester, the aryl esters, particularly phenyl ester and the aryl lower alkyl esters, particularly benzyl ester.
The term "alkyl" alone or in combination relates to a cyclic, branched or straight-chain monovalent hydrocarbon group containing one to twenty four, preferably one to twelve, carbon atoms. The term "lower-alkyl" is concerned with straight-chain or branched saturated alkyl groups with 1 to 8, preferably 1-4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, pentyl, hexyl, heptyl, octyl and the like.
Alkyl and lower-alkyl groups can optionally carry one or more substituents selected from alkyl, alkoxy, lower-alkyl, halogen, hydroxy, amino, nitro, thio and the like.
The term "halogen" stands for fluorine, chlorine, bromine or iodine.
In the specific oxazolidine of formula II, when R2 is an amino protecting group, any conventional amino protecting group can be utilized. These conventional amino protecting groups can be removed by methods well known in the art, including acid hydrolysis and catalytic hydrogenation. These conventional amino protecting groups include lower alkyl carbonyl, aryloxycarbonyl, halo substituted lower alkoxy carbonyl and arylloweralkoxycarbonyl, for example benzyloxycarbonyl, t-butoxycarbonyl, etc. Amine, amide or urethane protecting groups embrace groups such as, for example, benzyl, benzoyl, allyl, acetyl or tert.butoxycarbonyl.
Where required, isolation and purification of the compounds obtained according to the process in accordance with the invention can be carried out using any suitable separation or purification method, for example by filtration, extraction, crystallization, column chromatography, preparative HPLC, thin-layer chromatography or combinations of these or other procedures which are known from the state of the art.
This invention will be better understood by reference to the following Examples. These examples are intended to illustrate the invention only, and should not be construed to limit in any way the invention which is defined in the claims which follow.
EXAMPLE 1
Manufacture of methyl (4S,5R)-4-benzyl-2-oxo-oxazolidine-5-carboxylate
A solution of 70.0 g of a 92:8 mixture of the (4S,5S)- and (4S,5R)-isomers of methyl 4-benzyl-2-oxo-oxazolidine-5-carboxylate and 7.0 g of potassium tert.butylate in 700 ml of THF was stirred at 20° C. for four hours and at 45° C. for 2 hours, the solution was washed twice with semi-saturated sodium chloride solution, dried over MgSO4, filtered and the filtrate was evaporated to give 68 g (97%) of 95% methyl (4S,5R)-4-benzyl-2-oxo-oxazolidine-5-carboxylate (tlc (SiO2, ethyl acetate):Rf =0.5).
EXAMPLE 2
Manufacture of methyl (4S,5R)-4-cyclohexylmethyl-2-oxo-oxazolidine-5-carboxylate
For the manufacture of the aforementioned compound, methyl (4S,5S)-4-cyclohexylmethyl-2-oxo-oxazolidine-5-carboxylate, obtainable by hydrogenating methyl (4S,5R)-4-benzyl-2-oxo-oxazolidine-5-carboxylate, is reacted under the conditions given in Example 1. Methyl (4S,5R)-4-cyclohexylmethyl-2-oxo-oxazolidine-5-carboxylate is obtained in a yield of about 95%.

Claims (14)

What is claimed is:
1. A process for isomerizing a compound containing a (4,5)-cis-2-oxo-oxazolidine ring to the corresponding compound containing a (4,5)-trans-2-oxo-oxazolidine ring, comprising treating the (4,5)-cis compound with a strong base to give the (4,5)-trans compound.
2. A process for producing (4,5)-trans-2-oxo-oxazolidines, which process comprises treating a (4,5)-cis-2-oxo-oxazolidine of the structure: ##STR3## wherein R1 is benzyl or isobutyl,
R2 is an acid protecting group; and
R3 is an amino protecting group,
with a strong base to give a (4,5)-trans-2-oxo-oxazolidine of the structure: ##STR4##
3. The process according to claim 2, wherein the amino protecting group is an amine, an amide, or a urethane.
4. The process according to claim 2, wherein the acid protecting group is an alkyl group.
5. The process according to claim 2, wherein R2 is a lower-alkyl group and R3 is hydrogen or a benzyl, benzoyl, acetyl or allyl group.
6. The process according to claim 5, wherein R3 is hydrogen.
7. The process according to claim 2, wherein R1 is isobutyl.
8. The process according to claim 2, wherein R1 is benzyl.
9. The process according to claim 2, wherein the strong base is an alkali metal alcoholate, an alkaline earth metal alcoholate, a lithium amide, a sodium amide, a potassium amide, an alkyllithium compound, or an alkylmagnesium halide.
10. The process according to claim 2, wherein the strong base is sodium methylate or potassium tert.butylate.
11. The process according to claim 2, wherein the treating with the strong base is carried out at a temperature of -20° C. to +80° C.
12. The process according to claim 11, wherein the temperature is +20° C. to +45° C.
13. The process according to claim 2, wherein the treatment is carried out in the presence of a solvent selected from the group consisting of toluene, tetrahydrofuran and an alcohol.
14. The process according to claim 2, wherein the (4,5)-cis-2-oxo-oxazolidine is present in a mixture with its corresponding (4,5)-trans-2-oxo-oxazolidine at the start of the treatment.
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Publication number Priority date Publication date Assignee Title
EP2266607A2 (en) 1999-10-01 2010-12-29 Immunogen, Inc. Immunoconjugates for treating cancer
EP2289549A2 (en) 1999-10-01 2011-03-02 Immunogen, Inc. Immunoconjugates for treating cancer
US20040181074A1 (en) * 2001-05-23 2004-09-16 Hiroshi Murao Process for producing oxazolidinone derivative of beta-hydroxyethylamine compound and for producing beta-hydroxyethlamine compound
US7307184B2 (en) 2001-05-23 2007-12-11 Kaneka Corporation Processes for preparing oxazolidinone derivatives of β-hydroxyethlamine compounds and for preparing β-hydroxyethlamine compounds

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CN1152570A (en) 1997-06-25
KR100197459B1 (en) 1999-06-15

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